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Prof. Dr. Mirka Uhlirova

Principal Investigator, Institute for Genetics

Prof. Dr. Mirka Uhlirova
Principal Investigator, Institute for Genetics
Tel.  +49 221 478 84334
Mirka.Uhlirova[at]uni-koeln.de

Institut für Genetik
CECAD Forschungszentrum
Joseph-Stelzmann-Str. 26
50931 Köln
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Mirka Uhlirova

The Uhlirova laboratory uses the powerful genetic model of Drosophila melanogaster to understand how signaling pathways cooperate to ensure homeostasis at the cellular, tissue and whole-body level during normal development and under stress conditions. The group investigates how defects in signaling and regulatory circuits give rise to developmental abnormalities or disease states such as cancer and neurodegeneration.

Our research: The Uhlirova laboratory aims to understand the role of stress signaling in development, homeostasis, and disease states such as cancer and degenerative disorders. Using the relatively simple, yet relevant Drosophila model, the team focuses on characterizing the interplay between stress signaling modules and transcription factor networks. In particular, they are interested in determining how developmental and stress signals are translated into meaningful, context-specific responses via the regulation of target gene expression.

Our successes: The team identified the evolutionary conserved bZIP transcription factor Atf3 as a key regulator of metabolic and innate immune homeostasis. Using an established Drosophila epithelial tumor model, the group linked the aberrant activity of stress-inducible JNK signaling to enhanced invasiveness of tumors arising from oncogenic Ras activity and disrupted cell polarity. The JNK pathway promotes tumor malignancy through alteration of actin cytoskeleton dynamics and disruption of tissue architecture, highlighting the imapct of tissue mechanics in tumorigenesis. Lastly, the team discovered that the evolutionary conserved protein Ecdysoneless (Ecd) exerts an essential growth function by mediating pre-mRNA splicing.

Our goals: Current research projects attempt to dissect the role of stress signaling pathways and downstream transcription factors (TFs) in the regulation of growth, proliferation, cell death and cell migration. the group concentrates on functional characterization of individual TFs and TF networks downstream of stress-activated MAPK kinase signaling in the process of epithelial morphogenesis, tissue regeneration, wound healing, and tumorigenesis. Further, they explore a link between cellular stress induced by aberrant pre-mRNA splicing, cancer development, and neurodegeneration. Unraveling the molecular mechanisms that orchestrate stress responses is crucial for understanding normal physiology, diseases, and aging.

Our methods/techniques: The scientists take advantage of the genetic accessibility of the Drosophila model that facilitates gene discovery, in vivo analysis of gene function and gene interactions.
To gain mechanistic insights into a relationship between pathways and their components the scientists combine genetics with cell and molecular biology techniques, biochemistry, and genomic approaches. Collaborations with mouse and human geneticists are crucial to translate their findings to the context of human physiology and diseases.

Figures
Figure 1
Figure 2

Figure 1: Fat body-specific gain of Atf3 produces lean larvae whose fat body cells are filled with smaller lipid droplets compared to control (insets).

Figure 2: Loss of mechanical tension due to deficiency of the actin cross-linking protein Filamin/Cheerio causes downregulation of the Yorkie target gene expression as measured by the expanded::lacZ reporter activity (blue), in mosaic rasV12 scrib1cher1 imaginal discs compared to those bearing fully malignant rasV12 scrib1 clonal tumors. Model summarizing pleiotropic functions of JNK signaling in malignant tumors induced by Ras activation and polarity loss. Our data show that JNK promotes malignancy downstream of disturbed polarity by modulating tumor microenvironment (MMP1), tumor stiffness and survival (Cher).

EXTERNAL Cooperations
  • Prof. Dr. M. Jindra, Biology Center AS CR, Budweiss, CZ
  • Prof. Dr. J. Schultze, LIMES, Bonn, DE
  • Dr. D. Stanek, IMG AS CR, Prague, CZ
  • Prof. Dr. T. Tüting, Bonn, DE
  • Prof. Dr. B. Wirth, University of Cologne, DE